Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data

Abstract

Background: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns.Methods: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models.Results: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PDnormal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of

The effect of single low-dose primaquine treatment for uncomplicated Plasmodium falciparum malaria on hemoglobin levels in Ethiopia: a longitudinal cohort study

“…The ndings of this study were consistent with those of previous studies indicating low safety concerns associated with SLD-PQ in G6PDd malaria patients [19,22,27,55]. Similarly, a recent systematic review [56] reported that the hemolytic effects of SLD-PQ (0.1 and 0.25 mg/kg) were less likely in individuals who received G6PDd than in those who received a previous dose of 0.75 mg/kg.…”

“…The risk of anemia is likely to increase in individuals with lower pretreatment Hb concentrations [26]. Although PQ is linked to a brief reduction in Hb levels in G6PDd patients, baseline Hb levels continue to be the leading cause of anemia in such patients [27]. Additionally, severe hemolytic events might be rare and unlikely to be observed in small safety studies [22].…”

Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria

“…Supporting the WHO recommendation are several studies showing that SLDPQ is well tolerated in patients with African 8 , 9 and southeast Asian 10 G6PD variants. 11 Dose-dependent transmission blocking efficacy and reductions in gametocyte carriage have also been demonstrated with Dicko et al. suggesting a transmission blocking effect in individuals aged ≥5 years at doses ≥0.125 mg/kg of primaquine.…”

Artemether-lumefantrine with or without single-dose primaquine and sulfadoxine-pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reducePlasmodium falciparumtransmission: a phase 2 single-blind randomised clinical trial in Ouelessebougou, Mali

“…A pooled analysis of post treatment microscopy data indicated that artemether-lumefantrine may be the most potent ACT in terms of gametocyte clearance whilst gametocyte persistence is markedly longer after the drug combination dihydroartemisinin-piperaquine. 2 Importantly, post-treatment gametocyte carriage is an imperfect approximation of malaria transmission potential. Transmissible gametocytes may persist at submicroscopic densities after treatment and some antimalarial drugs may sterilize gametocytes before these are removed from the circulation.…”